This invention is concerned with novel (6a.alpha.,10a.alpha.,11a.alpha.)-2-(2-pyridinyl)-1,3,4,6,6a,7,8,9,10,10a, 11,11a-dodecahydro-2H-pyrazino[1,2-b]isoquinoline and derivatives or pharmaceutically acceptable salts thereof which have antidepressant activity and the ability to counteract the sedative side effect of antihypertensive agents. It also relates to a process for preparing the novel compounds, pharmaceutical compositions comprising the novel compounds and to a method of treating depression or antihypertensive agent induced sedation with the novel compounds.
2-Piperazinyl-5 (and/or 6)-substituted pyridines (U.S. Pat. No. 4,078,063) are known anorexigenic agents which are also said to have antidepressant activity by virtue of their pharmacological influence on serotonin levels.
Now, with the present invention there is provided (6a.alpha.,10a.alpha.,11a.alpha.)-2-(2-pyridinyl)-1,3,4,6,6a,7,8,9,10,10a, 11,11a-dodecahydro-2H-pyrazino[1,2-b]isoquinoline and derivatives which are antidepressant agents and have the ability to counteract the sedative effect of antihypertensive agents by virtue of their ability to selectively antagonize .alpha..sub.2 -adrenergic receptor sites.
The concept that the complex clinical state of depression is linked to a functional deficiency of monoamines in the central nervous system is now widely accepted. Numerous biochemical and clinical observations support the proposal that many forms of depressive illness are associated with reductions in adrenergic activity at functionally important sites in the brain. Thus, classical antidepressive drugs, such as amitriptyline and imipramine, are believed to act by blocking the neuronal reuptake of norepinephrine and/or serotonin, thereby enhancing the availability of the monoamines as neuro-transmitters.
In addition to .alpha..sub.1 -adrenergic receptors which mediate postsynaptic responses to the neurotransmitter norepinephrine, other adrenergic receptors are present at or near sympathetic terminals. These latter receptors, .alpha..sub.2 -adrenergic receptors, form part of a negative feedback system which modulates sympathetic neurotransmission by controlling the impulse-induced release of norepinephrine from presynaptic terminals. Activation of .alpha..sub.2 -adrenergic receptors results in a decrease in the amount of norepinephrine normally released from the nerve terminals by nerve impulses while antagonism of .alpha..sub.2 -adrenergic receptors increases norepinephrine release. Therefore, molecules that block .alpha..sub.2 -adrenergic receptors afford an alternate approach to enhancement of noradrenergic function and the treatment of depression associated with an absolute or relative deficiency of adrenergic function.
Mianserin, a clinically effective antidepressant which has been reported to have minimal in vivo norepinephrine reuptake inhibiting properties, blocks .alpha..sub.2 -adrenergic receptors. However, mianserin fails to exhibit any important selectivity for .alpha..sub.1 - or .alpha..sub.2 -adrenergic receptors suggesting that mianserin, in vivo, blocks .alpha..sub.1 -receptors at about the same dose required to block .alpha..sub.2 -receptors (Clineschmidt et al., Arch. Int. Pharmacodyn. Ther., 242, 59 (1979)).
The compounds of the present invention, being highly selective for the .alpha..sub.2 -adrenergic receptor, have definite therapeutic advantages over the more non-selective .alpha..sub.1 -, .alpha..sub.2 -antagonists. Since .alpha..sub.1 - (or post-synaptic) blockade opposes the increase in nor-adrenergic transmission initiated through .alpha..sub.2 -blockade, compounds that selectively antagonize .alpha..sub.2 -adrenergic receptors promote enhanced neurotransmission at nor-adrenergic synapses. In addition, molecules with reduced .alpha..sub.1 -receptor blocking properties, such as the compounds of the present invention, produce less orthostatic hypotension, an undesirable side-effect (Synder, Pharmakopsychiat, 13, 62 (1980)).
Sedation, the limiting side effect produced by some antihypertensive agents, is believed to be associated with stimulation of presynaptic .alpha..sub.2 -adrenergic receptors. However, the lowering of blood pressure is not related to these receptors, but rather to postsynaptic adrenergic receptors (Birch et al., Br. J. Pharmacol., 68, 107P (1979)). Selective .alpha..sub.2 -receptor antagonists should be useful in reducing the adverse effect of sedation produced by some antihypertensive drugs. Thus, the selective .alpha..sub.2 -receptor blocker, yohimbine, antagonizes the sedation produced by clonidine (Drew et al., Br. J. Pharmacol., 67, 133 (1979)) and the locomotor depressant effects of methyldopa in rats (Clineschmidt et al., Arch. Int. Pharmacodyn. Ther., 244, 231 (1980)). In addition, yohimbine has been reported to reduce clonidine-induced sedation in man (Autret et al., Eur. J. Clin. Pharmacol., 12, 319 (1977)).
The compounds of the present invention, being highly selective for the .alpha..sub.2 -adrenergic receptor, effectively reduce the sedative effects of antihypertensive agents without affecting the blood pressure lowering properties.